Extensions of previous work and new projects are proposed in four main areas: (1) Studies on preproinsulin structure and of the role of this precursor and related forms in the biosynthesis and segregation of insulin, comparative studies on preproinsulin, proinsulin and C-peptide structures in man and in primitive vertebrates, studies on precursors of other islet hormones including especially glucagon and somatostatin, further characterization of insulin mRNA and studies via molecular cloning of the structure and nucleotide sequence of both insulin mRNA and the chromosomal genes which code for insulin and/or other islet hormones in rats and other species. (2) Further studies on insulin binding, degradation and action in target tissues such as hepatocytes and heptoma cells including studies on the mode of proteolytic cleavage of the hormone, characterization of the degradation fragments, efforts to clarify the relationship between insulin action and the endocytotic processes involved in receptor-mediated insulin uptake and degradation, further efforts to isolate and characterize insulin receptors through the use of specific cross-linking reagents, studies on insulin receptor antibodies and on insulin effects in isolated plasma membrane preparations and other resolved systems. (3) Further studies on the propagation of islet cell tumors in vivo and in vitro and on factors which regulate beta cell replication in cultured adult islets of Langerhans, and efforts to develop endocrine cell lines from human and animal islet tumors. (4) Studies on isolated islet cells from rats and mice with emphasis on the development of methods for separating islet cell subpopulations by means of cell sorting and further studies on the characterization of islet cell plasma membranes with regard especially to their antigenic components and the nature and structure of these components. The pathogenetic significance of the circulating non-species specific islet cell antibodies which occur early in the course of insulin-dependent diabetes will be studied using isolated beta cell suspensions and cultured islets of Langerhans from several species.